The present invention is directed to a process for preparing 5-fluorouracil, and to a novel starting compound, 2,4,5-trifluoropyrimidine, used in the process.
U.S. Pat. Nos. 3,280,124 and 3,314,955 disclose that 2,4,6-trifluoropyrimidine can be obtained by reacting 2,4,6-trichloropyrimidine with anhydrous potassium fluoride at elevated temperatures, to provide the desired 2,4,6-trifluoropyrimidine in high yield with excellent purity.
U.S. Pat. No. 3,964,444 teaches, at column 2, lines 30-33, that chlorine or bromine substituents in the 5-position of the pyrimidine ring are exchanged for a fluorine substituent only with difficulty, or not at all. The patent deals with a process for exchanging fluorine for chlorine or bromine substituents in compounds such as 2,4,5,6-tetrachloro- or bromo-pyrimidine, or 2,4,6-trichloro- or bromo-pyrimidine, by action of anhydrous hydrofluoric acid under mild conditions. The art would not expect the 5-position halogen atom to be involved in an exchange reaction with fluorine.
U.S. Pat. No. 2,937,171 discloses 2,4,5-tribromopyrimidine as a starting compound (Example XV), which is reacted with SF.sub.4 to exchange fluorine for halogen. The patentee indicates that the mechanism of the reaction is not exactly known, but that at least one chlorine or bromine atom is displaced with fluorine (note column 3, lines 8-19). However, U.S. Pat. No. 3,280,124 discussed above discloses, at column 1, lines 20-26, that when an attempt was made to fluorinate 2,4,6-trichloropyrimidine by means of sulfur tetrafluoride, only mixtures of partly fluorinated pyrimidines were obtained. This would suggest that only partially fluorinated compounds would be obtained in an attempt to react 2,4,5-tribromopyrimidine with sulfur tetrafluoride, especially in view of the well-known difficulty of displacing halogen substituents at the 5-position, as borne out by U.S. Pat. No. 3,694,444 at column 2, lines 30 et seq.
M. J. Langerman and C. K. Banks, J. Am. Chem. Soc., 73, 3011 (1951) relates to preparing 2,4,6-trisubstituted pyrimidines, and has no disclosure of any compounds having a substituent in the 5-position.
H. Schroeder, E. Kober, H. Ulrich, R. Ratz, H. Agahigian and C. Grundman, J. Org. Chem. 27, 2580 (1952) discloses attempts to convert tetrachloropyrimidine into tetrafluoropyrimidine, with all attempts to replace the chlorine atom in the 5-position with fluorine being a failure. The product produced by reaction of tetrachloropyrimidine with silver fluoride was 5-chloro-2,4,6-trifluoropyrimidine. Tetrafluoropyrimidine was finally obtained by reacting 2,4,6-trichloropyrimidine with silver fluoride to produce 2,4,6-trifluoropyrimidine, which was in turn reacted with silver difluoride to form the desired tetrafluoropyrimidine. As is clear from the results reported by Schroeder et al, the displacement of the halogen in the 5-position by fluorine is most difficult.
R. E. Banks, D. S. Field and R. H. Haszeldine, J. Chem. Soc. (C), 1822 (1967) discusses the results of nucleophilic attack upon tetrafluoropyrimidine. Banks et al indicate, in the second paragraph of the article, that the fluorine substituent in the 5-position resists displacement from tetrafluoropyrimidine. The only aqueous hydrolysis step disclosed in the Banks reaction schemes, set forth on page 1823 of the article, is reaction (i), which displaces fluorine with a hydroxyl radical at the 4-position. Other reactions relate to the displacement of fluorine atoms by a methoxy group, with the methoxy group displacing, in order, the fluorine substituents in the 4-position, the 6-position, and the 2-position, with no apparent attack at the 5-position. Those in the art would not be able to gauge the effect on the activity of the 5-position in compounds lacking the 6-position fluorine atom. For instance, the difference in behavior between the trichloropyrimidine and the tetrachloropyrimidine of the Schroeder et al article, discussed above, serves to further illustrate the unpredictability of the trifluorinated product.
U.S. Pat. No. 4,140,857 discloses a process for preparing 2,4,5-trichloropyrimidine by reacting N,N'-bis-(2-cyanoethyl)-thioperoxy dicarboxylic acid diamides with chlorine at temperatures of from 0.degree. to 40.degree. C. The reaction mixture is then subsequently heated in the absence of chlorine to temperatures of 100.degree. to 150.degree. C. to form the desired compound.